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Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR

Author

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  • Deepika Vasudevan

    (New York University Grossman School of Medicine)

  • Sarah D. Neuman

    (University of Wisconsin-Madison)

  • Amy Yang

    (New York University Grossman School of Medicine)

  • Lea Lough

    (New York University Grossman School of Medicine)

  • Brian Brown

    (New York University Grossman School of Medicine)

  • Arash Bashirullah

    (University of Wisconsin-Madison)

  • Timothy Cardozo

    (New York University Grossman School of Medicine)

  • Hyung Don Ryoo

    (New York University Grossman School of Medicine)

Abstract

The Integrated Stress Response (ISR) helps metazoan cells adapt to cellular stress by limiting the availability of initiator methionyl-tRNA for translation. Such limiting conditions paradoxically stimulate the translation of ATF4 mRNA through a regulatory 5′ leader sequence with multiple upstream Open Reading Frames (uORFs), thereby activating stress-responsive gene expression. Here, we report the identification of two critical regulators of such ATF4 induction, the noncanonical initiation factors eIF2D and DENR. Loss of eIF2D and DENR in Drosophila results in increased vulnerability to amino acid deprivation, susceptibility to retinal degeneration caused by endoplasmic reticulum (ER) stress, and developmental defects similar to ATF4 mutants. eIF2D requires its RNA-binding motif for regulation of 5′ leader-mediated ATF4 translation. Consistently, eIF2D and DENR deficient human cells show impaired ATF4 protein induction in response to ER stress. Altogether, our findings indicate that eIF2D and DENR are critical mediators of ATF4 translational induction and stress responses in vivo.

Suggested Citation

  • Deepika Vasudevan & Sarah D. Neuman & Amy Yang & Lea Lough & Brian Brown & Arash Bashirullah & Timothy Cardozo & Hyung Don Ryoo, 2020. "Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18453-1
    DOI: 10.1038/s41467-020-18453-1
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    Cited by:

    1. Ramona Weber & Leon Kleemann & Insa Hirschberg & Min-Yi Chung & Eugene Valkov & Cátia Igreja, 2022. "DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Katharina Clemm von Hohenberg & Sandra Müller & Sibylle Schleich & Matthias Meister & Jonathan Bohlen & Thomas G. Hofmann & Aurelio A. Teleman, 2022. "Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Yoshifumi Sonobe & Jihad Aburas & Gopinath Krishnan & Andrew C. Fleming & Ghanashyam Ghadge & Priota Islam & Eleanor C. Warren & Yuanzheng Gu & Mark W. Kankel & André E. X. Brown & Evangelos Kiskinis , 2021. "A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Ying Xue & Fujia Lu & Zhenzhen Chang & Jing Li & Yuan Gao & Jie Zhou & Ying Luo & Yongfeng Lai & Siyuan Cao & Xiaoxiao Li & Yuhan Zhou & Yan Li & Zheng Tan & Xiang Cheng & Xiong Li & Jing Chen & Weimi, 2023. "Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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